Peripheral defects precede neuromuscular pathology in the Smn2B/- mouse model of spinal muscular atrophy

Abstract

Background: Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative disease caused by the loss or mutation of the survival motor neuron 1 (SMN1) gene. Though classically regarded as a motor neuron disorder, reports are increasingly describing the involvement of non-neuronal organs in SMA. The Smn^2B/- mouse is a model of SMA that displays a peripheral phenotype including metabolic defects.

Objective: Here, we characterized several neuronal and non-neuronal defects in the Smn^2B/- mouse throughout development to better understand the progression of the disease and the relationship between tissue defects.

Methods: We collected tissues from mutant Smn^2B/- mice and Smn^2B/+ littermate controls at several timepoints and evaluated spinal cord motor neuron loss, neuromuscular junction pathology, muscle fiber size, liver steatosis, and pancreatic islet cell composition. Blood glucose and plasma neurofilament light chain (NfL) were also measured.

Results: Smn^2B/- mice displayed several peripheral defects prior to motor neuron loss and showed early elevations in neurofilament light chain (NfL) protein.

Conclusions: This work provides an important framework for guiding future research with this mouse model and demonstrates that the liver may be an early target in the development of SMA.

Keywords: animal models; biomarkers; blood glucose; liver; metabolism; motor neurons; muscles; neurofilament protein; neuromuscular junction; pancreas.